The Epstein-Barr virus (EBV) has been implicated in a number of human tumors, and is of interest in the development of anti-tumor therapies. EBV associated diseases often arise from a failure of the host immune response to control the proliferation of latently infected cells. During the persistent stage of EBV infection, the virus primarily infects long-lived memory B cells in the periphery. Latent EBV infection of B cells is associated with rapid tumor development in immunocompromised individuals, such as bone marrow transplant recipients and persons with AIDS.
Burkitt's lymphoma (BL) has likewise been linked to immunosuppression in AIDS, and to malarial infection in the case of endemic BL. All cases of Burkitt's lymphoma are also marked by the presence of specific chromosomal translocations, which result in the activation of the c-myc proto-oncogene. The majority of these involve a reciprocal translocation between chromosome 8 at or near the site of the c-myc locus, and the immunoglobulin heavy chain locus on chromosome 14. Other EBV associated tumors include Hodgkin's disease, certain unusual types of T cell lymphoma, and nasopharyngeal carcinoma.
EBV is a gamma herpesvirus of the Lymphocryptovirus (LCV) genus. The EBV genome is composed of linear double-stranded DNA, approximately 172 kilobase pairs (kb) in length. EBV has a series of 0.5 kb terminal direct repeats and internal repeat sequences that divide the genome into short and long, largely unique sequence domains. EBV was the first herpesvirus to have its genome completely cloned and sequenced. There are two major types of EBV isolate, called types 1 and 2, which appear to be identical over the bulk of the EBV genome but show allelic polymorphism in a subset of latent genes, including EBNA-LP.
EBV infects the majority of the World's adult population and following primary infection the individual remains a lifelong carrier of the virus. In underdeveloped countries, primary infection with EBV usually occurs during the first few years of life and is often asymptomatic. However, in developed populations, primary infection is more frequently delayed until adolescence or adulthood, in many cases producing the characteristic clinical features of infectious mononucleosis. EBV is orally transmitted, and infectious virus can be detected in oropharyngeal secretions from infectious mononucleosis patients, from immunosuppressed patients and at lower levels from healthy EBV seropositive individuals. Early in the course of primary infection, EBV infects B-lymphocytes. EBV does not usually replicate in B-lymphocytes but instead establishes a latent infection, which is characterized by the limited expression of a subset of virus genes.
Several viruses have recently come forth as both vehicles for gene therapy and as candidate anticancer agents. Among them adenovirus, a mildly pathogenic human virus that propagates prolifically in epithelial cells, the origin of many human cancers. Adenovirus has emerged as a virus that can be engineered with oncotropic properties. See, for example, U.S. Pat. Nos. 5,846,945; 5,801,029; 5,747,469; PCTUS1999/08592 (WO 99/59604;) or PCT/US1998/03514 (WO 98/35554;); PCT/US1997/22036 (WO 98/29555;). Replication competent adenovirus vectors have been designed to selectively replicate in tumor cells. Improving the delivery of these adenoviruses, both to local-regional and disseminated disease, as well as improving the virus to promote intratumoral spread are of particular interest.
Several experimental cancer therapies utilize various aspects of adenovirus or adenovirus vectors. See, for example, U.S. Pat. Nos. 5,846,945; 5,801,029; PCT/US99/08592; U.S. Pat. No. 5,747,469; PCT/US98/03514; and PCT/US97/22036.
Although replication competent adenoviruses are able to achieve selective targeting and amplification for the treatment of some types of cancer, there remains a need for improvement in both the adenovirus vectors themselves and methods for their use with respect to particular types of cancers. Preliminary results suggest that effective treatment strategies may require development of specific adenovirus vectors and/or methods particular to the type of cancer under treatment.
There is, therefore, substantial interest in development of viral vectors that enable the targeting of EBV-positive cells in vivo. The uniform presence of the EBV genome in certain tumors, versus its presence in only a very small number of normal B cells, suggests that novel therapies which include specific targeting and cytolysis of EBV-positive cells may be effective for treating such tumors.
Publications
Feng et al. (2002) J. Virol. 76:10951-10959 discuss the use of adenovirus vectors expressing EBV immediate early proteins to treat EBV-positive tumors. Abdulkarim and Bourhis (2001) Lancet Oncol. 2:622-630 suggest that the use of antisense oligodeoxynucleotides against Epstein-Barr virus and human papillomavirus oncoproteins to effect downregulation of the oncoproteins can influence tumor cell growth and restore sensitivity to cytotoxic agents. Another approach uses antiviral drugs such as acyclic nucleoside phosphonates, in combination with chemotherapy.
Grinstein et al. (2002) Cancer Res 62(17):4876-8 suggest the presence of EBV in a variety of carcinomas, including those of the breast, lung, colon, and prostate. A review of EBV in human disease may be found in Murray and Young (2002) Frontiers in Bioscience 7:519-540.